CA1188224A - Compositions for treating glaucoma - Google Patents
Compositions for treating glaucomaInfo
- Publication number
- CA1188224A CA1188224A CA000405136A CA405136A CA1188224A CA 1188224 A CA1188224 A CA 1188224A CA 000405136 A CA000405136 A CA 000405136A CA 405136 A CA405136 A CA 405136A CA 1188224 A CA1188224 A CA 1188224A
- Authority
- CA
- Canada
- Prior art keywords
- carbon atoms
- composition
- butyl
- compound
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 35
- 208000010412 Glaucoma Diseases 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 29
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 23
- 230000004410 intraocular pressure Effects 0.000 claims abstract description 18
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 17
- 125000003118 aryl group Chemical group 0.000 claims abstract description 17
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000005466 alkylenyl group Chemical group 0.000 claims abstract description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 72
- -1 acetamido, amino Chemical group 0.000 claims description 35
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 14
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 14
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000000644 isotonic solution Substances 0.000 claims description 7
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 7
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 7
- 229960002216 methylparaben Drugs 0.000 claims description 7
- 239000003755 preservative agent Substances 0.000 claims description 7
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 7
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 7
- 229960003415 propylparaben Drugs 0.000 claims description 7
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 7
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 claims description 7
- 229940033663 thimerosal Drugs 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims 18
- 235000019445 benzyl alcohol Nutrition 0.000 claims 6
- 229960004217 benzyl alcohol Drugs 0.000 claims 6
- 229910052799 carbon Inorganic materials 0.000 claims 3
- 229910052739 hydrogen Inorganic materials 0.000 claims 3
- 239000001257 hydrogen Substances 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
- 239000002202 Polyethylene glycol Substances 0.000 claims 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 17
- 238000000034 method Methods 0.000 abstract description 15
- 230000001839 systemic circulation Effects 0.000 abstract description 7
- 241000124008 Mammalia Species 0.000 abstract description 5
- 239000012530 fluid Substances 0.000 abstract description 5
- 230000009885 systemic effect Effects 0.000 abstract description 3
- 210000001742 aqueous humor Anatomy 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 9
- 210000004185 liver Anatomy 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 239000002876 beta blocker Substances 0.000 description 7
- 229940097320 beta blocking agent Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 108090000371 Esterases Proteins 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000007071 enzymatic hydrolysis Effects 0.000 description 4
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 240000005578 Rivina humilis Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229940050410 gluconate Drugs 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229960005221 timolol maleate Drugs 0.000 description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 2
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- DYIOSHGVFJTOAR-JGWLITMVSA-N (2r,3r,4s,5r)-6-sulfanylhexane-1,2,3,4,5-pentol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CS DYIOSHGVFJTOAR-JGWLITMVSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 description 1
- 125000006031 2-methyl-3-butenyl group Chemical group 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 101100087530 Caenorhabditis elegans rom-1 gene Proteins 0.000 description 1
- 208000002061 Cardiac Conduction System Disease Diseases 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- 102100038916 Caspase-5 Human genes 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 101100112336 Homo sapiens CASP5 gene Proteins 0.000 description 1
- 101100273286 Mus musculus Casp4 gene Proteins 0.000 description 1
- 101100305983 Mus musculus Rom1 gene Proteins 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 206010057430 Retinal injury Diseases 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 description 1
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 229940030611 beta-adrenergic blocking agent Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 210000003123 bronchiole Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000007073 chemical hydrolysis Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229960001632 labetalol Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 235000011091 sodium acetates Nutrition 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical group [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
Landscapes
- Health & Medical Sciences (AREA)
- Emergency Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
COMPOSITIONS FOR TREATING GLAUCOMA Abstract of the Disclosure A method for the treatment of glaucoma or lowering intraocular pressure in a mammal, involving topically administering to the eye of such mammal a selectively metabolized beta-blocking compound of the formula wherein R may be lower alkyl, lower alkynyl, aryl, or aralkyl; A may be a direct bond, lower alkylenyl, or lower alkenyl; x may be an integer from 1 to 3; Ar may be substituted or unsubstituted aromatic; R1 may be lower alkyl, lower hydroxy alkyl, lower alkenyl, lower alkynyl, or aralkyl; and pharmaceutically accepted salts thereof. Because of a relatively long duration of action of such compounds in ocular fluids and a rela-tively short duration of action in the systemic circula-tion, such compounds are useful for the treatment of excessive intraocular pressure without substantial systemic side effects.
Description
8;~
Background of the Invention .
The present invention relates to a method for the treatment of glaucoma. More particularly, the invention relates to a novel method of treatment of glaucoma or lowering of intraocular pressure by topically administering beta-adrenergic blocking agents to the eye.
Glauco~a is a condition of the eye characterized by increased intraocular pressure. Untreated, the condition can event~ally lead to irreversible retinal damage and blindness. Conventional therapy for glaucoma has involved topical administration o~
pilocarpine and/or epinephrine, administered to the eye several times daily.
Various beta-blocking agents may also be used to lower intraocular pressure. Such use is described, for example, in reviews by W. P. Boger in Drugs, 18, 25-32 (1979) and by T. J. Zimmerman & W. p. Boger in Surv.
Ophthalaol., 23(c), 347 (1979). The use of b blockers for the treatment of glaucoma is also described in the patent literature. For example, U.S.
Patent No. ~,195,085 to Stone discloses a method for treatment of glaucoma by the ocular administration of a beta-blocking compound, timolol maleate. V.S. Patent No. 4,127,674 discloses treating glaucoma with labetalol, a known antagonist of both alpha and beta adrenergic receptors. However, these methods also possess significant drawbacks~ in that the absorption of the beta-blocking compound into the systemic circulation can cause undesirable side effects. Such side effects result from prolonged beta-blocking action on the heart, bronchioles and blood vessels. For example, according to Physicians' Desk Reference, Charles E. Baker, Jr~, 35th Edition, 1981, p. 1233, adverse reactions to the topical use o timolol maleate can include bronchospasm, heart failure, as well as cardiac conduction defects. Accordingly, there is a need for a method of treatment for glaucoma or for lowering intraocular pressure utilizing beta-blocking agents which are relatively free of unwanted systemic side-effects.
Certain beta-blockiny agents which contain enzymatically labile ester groups are known to exhibit short-acting beta-blocking effects in the systemic circulation. Such short-acting beta-blocking compounds (SABBs) have been suggested for treatment or prophylaxis of cardiac disorders as a means for reducing heart work or improving rhythmicity for a short duration. Such short-acting beta-blocking compounds avoid the sometimes counterproductive effects of conventional beta-blocking agents, whose effects are typically long-lived and, therefore, difficult to precisely control.
Summar~ of the Invention In accordance with the present invention, disclosed herein is a method for the treatment of glaucoma or for lowering intraocular pressure in a mammal, comprising topically administering to the eye of such mammal a b_ -blocking compound of the formula:
~ Ol OH
R-O-C - A Ar-O-CH2-CH-CH2-NH-R
. x wherein R is lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower alkyl or aryl carboxy-methyl, lower haloalkyl, aralkyl or aryl; A is a direct bond, lower alkylenyl, or lower alkenyl; x is an integer from l to 3, provided that when x is greater than 1, di~ferent occurences of the R-O-C-A- group may be the same or different; Ar is unsubstituted aromatic or aro-matic substituted with lower alkyl~ lower alkenyl, lower ~3~
alkynyl, lower alkoxv, halogen, acetamido, amino, nitro, lower alkylamino, hydroxy, lower hydroxyalkyl or cyano;
R1 is lower alkyl, lower hydroxyalkyl, lower alkenyl, lower alkynyl or aralkyl; or a pharmaceutically acceptable salt thereo~.
Detailed Description of the Invention The above-mentioned short-acting beta-blocking compounds effectively reduce intraocular pressure in the eyes of mammals when topically administered. Because o~
their short-lived duration of action in the systemic circulation, side-effects produced by their migration out of the eye are consequently reduced. It has further been discovered that certain of these compounds show an increased longevity of effect when present in the ocular fluid, compared to the duration of their systemic effects. Consequently, the present invention resides in the treatment of glaucoma or lowering intraocular pressure with a beta-blocking compound which exhibits relatively long duration of action while in the ocular fluid, but which is subject to relatively rapid breakdown into inactive metabolites upon passage to the systemic circulation.
Compounds administered by the method of the present invention are represented by the formula:
_ OH
R-O-~ - A Ar-O-CH2-CH-CH2-NH-R1 wherein R represents lower alkyl of straight or branched carbon chains from 1 to about 10 carbon atoms, lower cycloalkyl of from 3 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkynyl of from 2 to about 5 carbon atoms, lower alkyl carboxymethyl in which the alkyl portion contains from 1 to about 5 carbon atoms, aryl carboxymethyl in which the aryl portion contains from 6 to about 8 carbon atoms, aryl of from 6 to about 10 carbon atoms or aralkyl wherein the a].kyl portion contains from about 1 to about 5 carbon atoms and the aryl portion represents substituted or unsubstituted monocyclic or polycyclic aromatic or heterocyclic ring systems of from 6 to about 10 carbon atoms; A represents a direct bond between the ester group and Ar, lower alkylenyl of from l to about 10 carbon atoms~ or alkenyl of from 2 to about 10 carbon atoms; x represents an integer from 1 to 3, provided that whe~ x is greater than 1, different occurrences of the R-O-~-A- ~roup may be the same or different; Ar represents substituted or unsubstituted aromatic, including monocyclic, polycyclic and heterocyclic ring systems, wherein aromatic substituents include lower alkyl of from 1 to about 10 carbon atoms, lower alkenyl of from 2 to about 10 carbon atoms, lower alkynyl of from 2 to about 10 carbon atoms, lower alkoxy of from 1 to about 10 carbon atoms, halogen, acetamido, amino, nitro, lower alkylamino, of ~rom 1 to about 10 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 10 carbon atoms, and cyano; R1 represents lower alkyl of from 1 to about 10 carbon atoms, such as methyl, propyl, hexyl, isopropyl, and the like; lower hydroxyalkyl of from 2 to about 10 carbon atoms, such as hydroxyethyl, hydroxy t-butyl, hydroxyisopropyl and the like; lower alkenyl of from 3 to about lO carbon atoms~ such as allyl; lower alkynyl of from 3 to about ~0 lO carbon atoms such as dimethylpropargyl and the like;
or aralkyl wherein the alkyl portion contains from 1 to about 5 carbon atoms and the aryl portion contains from ~ to about 10 carbon atoms, such as benzyl, phenethyl, naphthylethyl, 3,4-dimethoxyphenethyl and the like.
Such compounds may be administered as their pharmaceutically acceptable acid addition salts, e.g., .
as the hydrochloride, sulfate, phosphate, gluconate, tartrate, et cetera.
In preferred compounds, A is a direct bond, lower alkylenyl of from 3 to about 5 carbon atoms, such as methylene, ethylene, butylene and the like, or lower alkenyl of from 2 to about 5 carbon atoms, sueh as ethenyl, 2-propenyl, 2-butenyl, and the like and x is 1 or 2, and ir. particularly preferred compounds, Ar is phenyl, x is 1 or 2 and A is a direct bond, lower alkylenyl of from 1 to 3 earbon atoms, or lower alkenyl of 2 earbon atoms. It has been found that the compounds in which Ar is phenyl and para-substituted, beta-blocking poteney and shortness of duration of action in blood are improved when ~ is lower alkylene wi~h 1 or more carbons, i.e., the ester group is isolated from the aromatie ring by at least one methylene unit. Alterna-tively, in compounds in which Ar is phenyl, at least one of the ester-containing groups, R-O-C-, is advanta-geously in the ortho-position with respeet to the side chain. It is surprising and presently unexplained, that two configurations of the compounds of the present invention, para-substitution with an ester carbonyl iso-lated from the aromatie ring and ortho-substitution with the ester carbonyl attached directly to the aromatic ring, provide enhanced beta-bloeking poteney and relatively short duration of action in blood.
The ester substituent, R, in preferred compounds, is lower alkyl of from 1 to about 5 earbon atoms, such as methyl, ethy, n-butyl, n-pentyl, and the like; lower alkenyl of from 2 to about 5 earbon atoms, sueh as ethenyl, 2-propenyl,
Background of the Invention .
The present invention relates to a method for the treatment of glaucoma. More particularly, the invention relates to a novel method of treatment of glaucoma or lowering of intraocular pressure by topically administering beta-adrenergic blocking agents to the eye.
Glauco~a is a condition of the eye characterized by increased intraocular pressure. Untreated, the condition can event~ally lead to irreversible retinal damage and blindness. Conventional therapy for glaucoma has involved topical administration o~
pilocarpine and/or epinephrine, administered to the eye several times daily.
Various beta-blocking agents may also be used to lower intraocular pressure. Such use is described, for example, in reviews by W. P. Boger in Drugs, 18, 25-32 (1979) and by T. J. Zimmerman & W. p. Boger in Surv.
Ophthalaol., 23(c), 347 (1979). The use of b blockers for the treatment of glaucoma is also described in the patent literature. For example, U.S.
Patent No. ~,195,085 to Stone discloses a method for treatment of glaucoma by the ocular administration of a beta-blocking compound, timolol maleate. V.S. Patent No. 4,127,674 discloses treating glaucoma with labetalol, a known antagonist of both alpha and beta adrenergic receptors. However, these methods also possess significant drawbacks~ in that the absorption of the beta-blocking compound into the systemic circulation can cause undesirable side effects. Such side effects result from prolonged beta-blocking action on the heart, bronchioles and blood vessels. For example, according to Physicians' Desk Reference, Charles E. Baker, Jr~, 35th Edition, 1981, p. 1233, adverse reactions to the topical use o timolol maleate can include bronchospasm, heart failure, as well as cardiac conduction defects. Accordingly, there is a need for a method of treatment for glaucoma or for lowering intraocular pressure utilizing beta-blocking agents which are relatively free of unwanted systemic side-effects.
Certain beta-blockiny agents which contain enzymatically labile ester groups are known to exhibit short-acting beta-blocking effects in the systemic circulation. Such short-acting beta-blocking compounds (SABBs) have been suggested for treatment or prophylaxis of cardiac disorders as a means for reducing heart work or improving rhythmicity for a short duration. Such short-acting beta-blocking compounds avoid the sometimes counterproductive effects of conventional beta-blocking agents, whose effects are typically long-lived and, therefore, difficult to precisely control.
Summar~ of the Invention In accordance with the present invention, disclosed herein is a method for the treatment of glaucoma or for lowering intraocular pressure in a mammal, comprising topically administering to the eye of such mammal a b_ -blocking compound of the formula:
~ Ol OH
R-O-C - A Ar-O-CH2-CH-CH2-NH-R
. x wherein R is lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower alkyl or aryl carboxy-methyl, lower haloalkyl, aralkyl or aryl; A is a direct bond, lower alkylenyl, or lower alkenyl; x is an integer from l to 3, provided that when x is greater than 1, di~ferent occurences of the R-O-C-A- group may be the same or different; Ar is unsubstituted aromatic or aro-matic substituted with lower alkyl~ lower alkenyl, lower ~3~
alkynyl, lower alkoxv, halogen, acetamido, amino, nitro, lower alkylamino, hydroxy, lower hydroxyalkyl or cyano;
R1 is lower alkyl, lower hydroxyalkyl, lower alkenyl, lower alkynyl or aralkyl; or a pharmaceutically acceptable salt thereo~.
Detailed Description of the Invention The above-mentioned short-acting beta-blocking compounds effectively reduce intraocular pressure in the eyes of mammals when topically administered. Because o~
their short-lived duration of action in the systemic circulation, side-effects produced by their migration out of the eye are consequently reduced. It has further been discovered that certain of these compounds show an increased longevity of effect when present in the ocular fluid, compared to the duration of their systemic effects. Consequently, the present invention resides in the treatment of glaucoma or lowering intraocular pressure with a beta-blocking compound which exhibits relatively long duration of action while in the ocular fluid, but which is subject to relatively rapid breakdown into inactive metabolites upon passage to the systemic circulation.
Compounds administered by the method of the present invention are represented by the formula:
_ OH
R-O-~ - A Ar-O-CH2-CH-CH2-NH-R1 wherein R represents lower alkyl of straight or branched carbon chains from 1 to about 10 carbon atoms, lower cycloalkyl of from 3 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkynyl of from 2 to about 5 carbon atoms, lower alkyl carboxymethyl in which the alkyl portion contains from 1 to about 5 carbon atoms, aryl carboxymethyl in which the aryl portion contains from 6 to about 8 carbon atoms, aryl of from 6 to about 10 carbon atoms or aralkyl wherein the a].kyl portion contains from about 1 to about 5 carbon atoms and the aryl portion represents substituted or unsubstituted monocyclic or polycyclic aromatic or heterocyclic ring systems of from 6 to about 10 carbon atoms; A represents a direct bond between the ester group and Ar, lower alkylenyl of from l to about 10 carbon atoms~ or alkenyl of from 2 to about 10 carbon atoms; x represents an integer from 1 to 3, provided that whe~ x is greater than 1, different occurrences of the R-O-~-A- ~roup may be the same or different; Ar represents substituted or unsubstituted aromatic, including monocyclic, polycyclic and heterocyclic ring systems, wherein aromatic substituents include lower alkyl of from 1 to about 10 carbon atoms, lower alkenyl of from 2 to about 10 carbon atoms, lower alkynyl of from 2 to about 10 carbon atoms, lower alkoxy of from 1 to about 10 carbon atoms, halogen, acetamido, amino, nitro, lower alkylamino, of ~rom 1 to about 10 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 10 carbon atoms, and cyano; R1 represents lower alkyl of from 1 to about 10 carbon atoms, such as methyl, propyl, hexyl, isopropyl, and the like; lower hydroxyalkyl of from 2 to about 10 carbon atoms, such as hydroxyethyl, hydroxy t-butyl, hydroxyisopropyl and the like; lower alkenyl of from 3 to about lO carbon atoms~ such as allyl; lower alkynyl of from 3 to about ~0 lO carbon atoms such as dimethylpropargyl and the like;
or aralkyl wherein the alkyl portion contains from 1 to about 5 carbon atoms and the aryl portion contains from ~ to about 10 carbon atoms, such as benzyl, phenethyl, naphthylethyl, 3,4-dimethoxyphenethyl and the like.
Such compounds may be administered as their pharmaceutically acceptable acid addition salts, e.g., .
as the hydrochloride, sulfate, phosphate, gluconate, tartrate, et cetera.
In preferred compounds, A is a direct bond, lower alkylenyl of from 3 to about 5 carbon atoms, such as methylene, ethylene, butylene and the like, or lower alkenyl of from 2 to about 5 carbon atoms, sueh as ethenyl, 2-propenyl, 2-butenyl, and the like and x is 1 or 2, and ir. particularly preferred compounds, Ar is phenyl, x is 1 or 2 and A is a direct bond, lower alkylenyl of from 1 to 3 earbon atoms, or lower alkenyl of 2 earbon atoms. It has been found that the compounds in which Ar is phenyl and para-substituted, beta-blocking poteney and shortness of duration of action in blood are improved when ~ is lower alkylene wi~h 1 or more carbons, i.e., the ester group is isolated from the aromatie ring by at least one methylene unit. Alterna-tively, in compounds in which Ar is phenyl, at least one of the ester-containing groups, R-O-C-, is advanta-geously in the ortho-position with respeet to the side chain. It is surprising and presently unexplained, that two configurations of the compounds of the present invention, para-substitution with an ester carbonyl iso-lated from the aromatie ring and ortho-substitution with the ester carbonyl attached directly to the aromatic ring, provide enhanced beta-bloeking poteney and relatively short duration of action in blood.
The ester substituent, R, in preferred compounds, is lower alkyl of from 1 to about 5 earbon atoms, such as methyl, ethy, n-butyl, n-pentyl, and the like; lower alkenyl of from 2 to about 5 earbon atoms, sueh as ethenyl, 2-propenyl,
2-methyl-3-butenyl and the like, lower alkynyl of from 3 to about 5 carbon atoms, sueh as propargyl, methylpropargyl and the like, or lower cyeloalkyl of from 3 to about 5 carbon atoms sueh as cyclopropyl, cyclopentyl, 2-methylcyclopropyl, and the like; Rl is preferably lower alkyl of from 1 to about 5 carbon atoms sueh as methyl, ethyl, propyl, t-butyl, pentyl and the likel lower hydroxyalkyl of from 1 to about 5 carbon atoms, such as hydroxyethyl, hydroxy-t-butyl, hydroxyisopro-pyl and the like; lower alkynyl of from 3 to about 5 carbon atoms such as propargyl, dimethylpropargyl and -the like; or aralkyl, wherein the alkyl portion con-tains from 1 to about 5 carbon atoms and the aryl por-tion contains from 6 to about 10 carbon atoms, such as benzyl, phenethyl, dimethoxyphenethyl, naphthylethyl, phenylbutyl, and the like.
Preferred aromatic substituents include lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitroJ lower alkylamino of from 1 to about 5 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms, and cyano. Particularly preferred aromatic substituents are lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, cyano, and alkoxy.
The compounds described herein, as well as their methods of preparation, are disclosed in co-pending Canadian Patent Application No. 390,966, filed Novem-ber 26, 1981. In addition, certain of the compounds which may be employed in the method of the present invention are known in the art. For instance, com-pounds of the above formula in which A is ethenyl are described in U.S. Patent 4,191,765 and in Japan-ese unexamined patent application (Kokai) 7400247 (see also Chemical Abstracts, 80, 95546W (1974)).
Compounds of the above formula in which Rl is 1,1-dimethyl-2-hydroxyethyl are described in British Pat-ent 1,364,280, and compounds in which Rl is dimethyl~
propargyl are described in British Patent 1,450,287.
The compounds of ~his invention are advantageously administered topically to the eye in the form of a solution, ointment, or solid insert such as is described in ~.S. Patent No. 4,195,085 to allow controlled or delayed release of the drug.
Formulations may contain the active compound, preferably, in the form of a soluble acid addition salt, in amounts ranging Erom about 0.01 to about lO~
by wt., preferably, from about 0.5~ to about 5% by wt.
Unit dosages of the active compound can range from about 0.001 to about 5.0 mg., preferably from about 0.05 to about 2.0 mg. The dosage administered to a patient will depend upon the patient's needs and the particular compounds employed.
Carriers used in the preparations of the present invention are preferably non-toxic pharmaceutical organic or inorganic compositions such as water;
mixtures of water and water-miscible solvents, such as lower alcohols; mineral oils; petroleum jellies; ethyl cellulose; polyvinylpyrrolidone and other conventional carriers. In addition, the pharmaceutical preparations may also contain additional components such as emulsifying, preserving, wetting and sterilizing agents. These include polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4000, 6,000 and 10,000, bacteriocidal components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl - ~ -sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetracetic acid, and the like.
Additionally, suitable ophthalmic vehicles can be used as carrier media for the present purpose including 5 conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like.
The method of treatment of this invention advantageously involves the topical administration of eye drops containing the active compound.
Formulations for eye drops preferably include the active compound as a soluble acid addition salt in a properly buffered, sterile, aqueous isotonic solution.
The compounds employed in the method of the present invention are ester group-containing beta-blockers that have a selective, localized, beta blocking effect in the eye after topical administration. Such compounds are thought to be rapidly metabolized by plasma and/or liver esterases into inactive by-products, upon entering the systemic circulation. It has been discovered that these same compounds are relatively stable in ocular fluids, i.e., 1acrimal fluids and aqueous humor.
Consequently, such compounds are useful for the treatment of glaucoma or for lowering intraocular pressure since they remain stable when topically applied to the eye but rapidly metabolize when subsequently absorbed into the systemic circulation.
Some of the compounds break down in the aqueous humor more rapidly than others. Such compounds may advantageously be employed when only a temporary reduction in intraocular pressure is desired, say for diagnostic procedures. Longer acting compounds are generally used for effecting longer-term reductions in -9~
intraocular pressure, such as is desired when treating chronic glaucoma. Thus, the method of the present invention provides a very useful therapeutic alternative for the treatment of glaucoma or for lowering intraocular pressure.
The in vitro studies hereinafter described indicate that the compounds used in the method of the present invention will undergo different rates of enzymatic hydrolysis depending on their location within the body (see Table I). For example, the compound of Example I is completely hydrolyzed within 60 minutes in liver homogenate while only 0.3%
hydrolyzed after one hour in aqueous humor, and only 1.3~ hydrolyzed after two hours. The compound of Example V is less stable in aqueous humor, hydrolyzing
Preferred aromatic substituents include lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitroJ lower alkylamino of from 1 to about 5 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms, and cyano. Particularly preferred aromatic substituents are lower alkyl of from 1 to about 5 carbon atoms, fluoro, chloro, cyano, and alkoxy.
The compounds described herein, as well as their methods of preparation, are disclosed in co-pending Canadian Patent Application No. 390,966, filed Novem-ber 26, 1981. In addition, certain of the compounds which may be employed in the method of the present invention are known in the art. For instance, com-pounds of the above formula in which A is ethenyl are described in U.S. Patent 4,191,765 and in Japan-ese unexamined patent application (Kokai) 7400247 (see also Chemical Abstracts, 80, 95546W (1974)).
Compounds of the above formula in which Rl is 1,1-dimethyl-2-hydroxyethyl are described in British Pat-ent 1,364,280, and compounds in which Rl is dimethyl~
propargyl are described in British Patent 1,450,287.
The compounds of ~his invention are advantageously administered topically to the eye in the form of a solution, ointment, or solid insert such as is described in ~.S. Patent No. 4,195,085 to allow controlled or delayed release of the drug.
Formulations may contain the active compound, preferably, in the form of a soluble acid addition salt, in amounts ranging Erom about 0.01 to about lO~
by wt., preferably, from about 0.5~ to about 5% by wt.
Unit dosages of the active compound can range from about 0.001 to about 5.0 mg., preferably from about 0.05 to about 2.0 mg. The dosage administered to a patient will depend upon the patient's needs and the particular compounds employed.
Carriers used in the preparations of the present invention are preferably non-toxic pharmaceutical organic or inorganic compositions such as water;
mixtures of water and water-miscible solvents, such as lower alcohols; mineral oils; petroleum jellies; ethyl cellulose; polyvinylpyrrolidone and other conventional carriers. In addition, the pharmaceutical preparations may also contain additional components such as emulsifying, preserving, wetting and sterilizing agents. These include polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4000, 6,000 and 10,000, bacteriocidal components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl - ~ -sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetracetic acid, and the like.
Additionally, suitable ophthalmic vehicles can be used as carrier media for the present purpose including 5 conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like.
The method of treatment of this invention advantageously involves the topical administration of eye drops containing the active compound.
Formulations for eye drops preferably include the active compound as a soluble acid addition salt in a properly buffered, sterile, aqueous isotonic solution.
The compounds employed in the method of the present invention are ester group-containing beta-blockers that have a selective, localized, beta blocking effect in the eye after topical administration. Such compounds are thought to be rapidly metabolized by plasma and/or liver esterases into inactive by-products, upon entering the systemic circulation. It has been discovered that these same compounds are relatively stable in ocular fluids, i.e., 1acrimal fluids and aqueous humor.
Consequently, such compounds are useful for the treatment of glaucoma or for lowering intraocular pressure since they remain stable when topically applied to the eye but rapidly metabolize when subsequently absorbed into the systemic circulation.
Some of the compounds break down in the aqueous humor more rapidly than others. Such compounds may advantageously be employed when only a temporary reduction in intraocular pressure is desired, say for diagnostic procedures. Longer acting compounds are generally used for effecting longer-term reductions in -9~
intraocular pressure, such as is desired when treating chronic glaucoma. Thus, the method of the present invention provides a very useful therapeutic alternative for the treatment of glaucoma or for lowering intraocular pressure.
The in vitro studies hereinafter described indicate that the compounds used in the method of the present invention will undergo different rates of enzymatic hydrolysis depending on their location within the body (see Table I). For example, the compound of Example I is completely hydrolyzed within 60 minutes in liver homogenate while only 0.3%
hydrolyzed after one hour in aqueous humor, and only 1.3~ hydrolyzed after two hours. The compound of Example V is less stable in aqueous humor, hydrolyzing
3.6~ after one hour, 13.4% after two hours.
The present invention is further illustrated by the following examples which are not intended to be limiting.
-10~
Examples I-V
The enzymatic hydrolysis rates o:E the following compounds were examined in dog blood, liver homogenate, and aqueous humor:
CH30-C-CH2CH2- ~ -0-CH2CH-CH2N~-CH2-C~ ~ OCH3 COMPOUND OF EXAMPLE I
(C ~3 -0-cH2-cH-cH2-NH
COMPOUND OF EXAMPLE II
CH30-C-CH2CH2- ~ -o-CH2-8H-CH2-NH-C~ ~HCl COMPOUND OF EXAMPLE III
O O CH2-CH-CH2-NH- ~
25CH30-C ~ CH3 COMPOUND OF EXAMPLE IV
CH30-C- ~ CH3 r COMPOUND OF EXAMPLE V
88;~
All of the compounds tested were synthesized in accordance with the examples of Canadian Patent Ap-plication No. 390,966. Acetonitrile was "HPLC" grade.
Distilled water was used to dissolve the compounds and 0.01 N HCl was used to dissolve compounds requiring an acidic pH for dissolutlon.
Fresh aqueous humor was collected from eyes of dogs using a 23 gauge needle while fresh dog blood was collected into heparinized Vacutainer tubes. Fxesh liver was homogenized in 0.9% NaCl using a Potter-Elveh~em Teflon pestle and glass homogenizer making a 25% (W/V) homogenate.
A 0.5 ml aliquot of dog aqueous humor, blood, or liver homogenate was incubated with 12.5 ~g 10.5 ml) of b _ -blocker in a Dubnoff shaking metabolic incubator at 37C for 60 and 120 minutes. Denatured tissue con-trols were prepared by adding 2.0 ml of acetonitrile into 0.5 ml of aqueous humor, blood, or liver homogenate to destroy esterase activities prior to addition of the beta-blockers. These controls were then incubated at 37C for 120 ninutes. After 60 and 120 minutes, the in-cubations were terminated by addition of 2 ml of aceto-nitrile and immediately mixed using a Vortex mixer to stop esterase activities.
All samples were centrifuged at 4000 RPM for 10 minutes to sediment denatured proteins. The resultant supernatants were transferred to WISP vials and ana-lyzed by high pressure liquid chromatography. The hy-drolysis of beta-blockers in aqueous humor, blood, and liver homogenate was determined by disappearance of the compounds. The extent o-f enzymatic hydrolysis in each tissue was determined by comparing the amount of each compound (absolute peak area) recovered at each time point to the amount of each compound (absolute peak area) in denatured tissue control and aqueous control samples.
All of the compounds examined were initially tested ~or chemical hydrolysis in 0.1 N potassium phosphate buffer, pH 7.40l and all were found to be stable for at least three hours (data not shown).
Table 1 summarizes the results of these experiments. The extent of hydrolysis is expressed in terms of the amount of each compound recovered after the incubation period relative to the amount of each compound recovered in the denatured tissue control Most of the SABBs were readily hydrolyzed very rapidly (55.5-98.~% in 120 minutes) when incubated with dog blood and liver homogenate. In contrast, all of the compounds tested were resistant to enzymatic hydrolysis by esterases in dog aqueous humor having hydrolysis rates of D.3-3.6~ in 60 minutes and 1.3-13.4% in 120 minutes.
Example VI
The intraocular pressure lowering effect o~ the compounds of this invention are demonstrated in rabbits with normotensive eyes.
Sterile, isotonic saline solutions of each of the compounds used in procedures of ~xamples I, II, III, IV, and V are prepared by dissolving 10 ! 30 and 100 mg.
samples of each of the active compounds in 1 ml. of saline to give 1%, 3% and 10% solutions with pH about 6.0~7Ø Free amines require one equivalent of HCl to effect dissolution.
The intraocular pressure lowering effect of each compound is determined by treating the eyes of healthy rabbits with the above solutions. Three rabbits are used to evaluate the effect of each drug concentration.
A standard dose of 50 ~1. of each drug solution is applied to one eye of each of the three rabbits.
Intraocular pressure of both eyes is measured with a pressure tonograph or a Mackay-Marg Tonometer before -13~
drug administration and at 15, 30~ 45, 60, 120, 180, 24Q, 300, 360, 420 and 480 min. after dosing. Control rabbits are treated similarly with sterile isotonic saline solution. Intraocular pressure lowering in the treated eyes is compared with the untreated eyes, with saline treated eyes and with predrug pressures. All of the test compounds show intraocular pressure-lowering activityO
Example VII
The experiment of Example VI is repeated in all essential details, except that the following compounds are tested:
~ -CH2cHcH2NHcH2cH2 ~ -OCH3 CH=CHCOOCH3 OCH3 ~ -ocH2cHcH2NHc~(CH3)2 CH=CHCOOCH3 ~ -ocH2cHcH2NH-c ~CH20H
~ IOH ICH3 -oc~2cHcH2NH-c-c--CH
COOCH
Each of the test compounds exhibit intraocular pressure-lowering activity.
Example VIII
The experiment of Example VI is repeated in all essential details, except that rabbits which have corticosteroid-induced ocular hypertension, as described by sonomi~ L., ~t al., Glaucoma, Eds. R. Pittscrick, A.D.S. Caldwell, Academic Press, New York, ppO 98-107 (1980), are substituted for the normotensive rabbits.
Each of the test compounds exhibit intraocular pressure-lowering activity in this model.
- 1 5 ~ 88~4 ~ o ~ ~Ln ~ ~r D
~ ~ ~ 1--1` C~
U~
g O O
O W ~ ~
D~1 ~:
m o ol ~ o ~: ~ ~ u~
O . . .
n ' ~D O ~ ~ ~ ~a~
~ D 0 tl4 0 .,, E~
0 D ~
m ~ ,, m ~ a o a li3 0 O O O O
,,u~ a ~ ~ O O O o O
Z ~ ~ ~ ~ ~ ~r W~ ~ ~
o o :a~ ~ tY; a 'tS ~ E~l a H E-~ ~ ~~:
U~ ~ ~ 1 O
Z ~ ~ a~ JJ
~ ~ ~P O O O . O
O ~ O O O O ~1 0 a ~; O ~D ~ ~ ~ ~ --a ~: ,, ~n C~ ~;
~ ~ ~ SJ
~ ~ ~ u~ 0~5 O . . . ~ ~
o 0 Z ~
m ~ a~
~ ~D O O 1` ~D
O
~ I~
0~
Z ~ ~
~ 5~ H ~
O st~ H1--1~> 0 ~ X H
a
The present invention is further illustrated by the following examples which are not intended to be limiting.
-10~
Examples I-V
The enzymatic hydrolysis rates o:E the following compounds were examined in dog blood, liver homogenate, and aqueous humor:
CH30-C-CH2CH2- ~ -0-CH2CH-CH2N~-CH2-C~ ~ OCH3 COMPOUND OF EXAMPLE I
(C ~3 -0-cH2-cH-cH2-NH
COMPOUND OF EXAMPLE II
CH30-C-CH2CH2- ~ -o-CH2-8H-CH2-NH-C~ ~HCl COMPOUND OF EXAMPLE III
O O CH2-CH-CH2-NH- ~
25CH30-C ~ CH3 COMPOUND OF EXAMPLE IV
CH30-C- ~ CH3 r COMPOUND OF EXAMPLE V
88;~
All of the compounds tested were synthesized in accordance with the examples of Canadian Patent Ap-plication No. 390,966. Acetonitrile was "HPLC" grade.
Distilled water was used to dissolve the compounds and 0.01 N HCl was used to dissolve compounds requiring an acidic pH for dissolutlon.
Fresh aqueous humor was collected from eyes of dogs using a 23 gauge needle while fresh dog blood was collected into heparinized Vacutainer tubes. Fxesh liver was homogenized in 0.9% NaCl using a Potter-Elveh~em Teflon pestle and glass homogenizer making a 25% (W/V) homogenate.
A 0.5 ml aliquot of dog aqueous humor, blood, or liver homogenate was incubated with 12.5 ~g 10.5 ml) of b _ -blocker in a Dubnoff shaking metabolic incubator at 37C for 60 and 120 minutes. Denatured tissue con-trols were prepared by adding 2.0 ml of acetonitrile into 0.5 ml of aqueous humor, blood, or liver homogenate to destroy esterase activities prior to addition of the beta-blockers. These controls were then incubated at 37C for 120 ninutes. After 60 and 120 minutes, the in-cubations were terminated by addition of 2 ml of aceto-nitrile and immediately mixed using a Vortex mixer to stop esterase activities.
All samples were centrifuged at 4000 RPM for 10 minutes to sediment denatured proteins. The resultant supernatants were transferred to WISP vials and ana-lyzed by high pressure liquid chromatography. The hy-drolysis of beta-blockers in aqueous humor, blood, and liver homogenate was determined by disappearance of the compounds. The extent o-f enzymatic hydrolysis in each tissue was determined by comparing the amount of each compound (absolute peak area) recovered at each time point to the amount of each compound (absolute peak area) in denatured tissue control and aqueous control samples.
All of the compounds examined were initially tested ~or chemical hydrolysis in 0.1 N potassium phosphate buffer, pH 7.40l and all were found to be stable for at least three hours (data not shown).
Table 1 summarizes the results of these experiments. The extent of hydrolysis is expressed in terms of the amount of each compound recovered after the incubation period relative to the amount of each compound recovered in the denatured tissue control Most of the SABBs were readily hydrolyzed very rapidly (55.5-98.~% in 120 minutes) when incubated with dog blood and liver homogenate. In contrast, all of the compounds tested were resistant to enzymatic hydrolysis by esterases in dog aqueous humor having hydrolysis rates of D.3-3.6~ in 60 minutes and 1.3-13.4% in 120 minutes.
Example VI
The intraocular pressure lowering effect o~ the compounds of this invention are demonstrated in rabbits with normotensive eyes.
Sterile, isotonic saline solutions of each of the compounds used in procedures of ~xamples I, II, III, IV, and V are prepared by dissolving 10 ! 30 and 100 mg.
samples of each of the active compounds in 1 ml. of saline to give 1%, 3% and 10% solutions with pH about 6.0~7Ø Free amines require one equivalent of HCl to effect dissolution.
The intraocular pressure lowering effect of each compound is determined by treating the eyes of healthy rabbits with the above solutions. Three rabbits are used to evaluate the effect of each drug concentration.
A standard dose of 50 ~1. of each drug solution is applied to one eye of each of the three rabbits.
Intraocular pressure of both eyes is measured with a pressure tonograph or a Mackay-Marg Tonometer before -13~
drug administration and at 15, 30~ 45, 60, 120, 180, 24Q, 300, 360, 420 and 480 min. after dosing. Control rabbits are treated similarly with sterile isotonic saline solution. Intraocular pressure lowering in the treated eyes is compared with the untreated eyes, with saline treated eyes and with predrug pressures. All of the test compounds show intraocular pressure-lowering activityO
Example VII
The experiment of Example VI is repeated in all essential details, except that the following compounds are tested:
~ -CH2cHcH2NHcH2cH2 ~ -OCH3 CH=CHCOOCH3 OCH3 ~ -ocH2cHcH2NHc~(CH3)2 CH=CHCOOCH3 ~ -ocH2cHcH2NH-c ~CH20H
~ IOH ICH3 -oc~2cHcH2NH-c-c--CH
COOCH
Each of the test compounds exhibit intraocular pressure-lowering activity.
Example VIII
The experiment of Example VI is repeated in all essential details, except that rabbits which have corticosteroid-induced ocular hypertension, as described by sonomi~ L., ~t al., Glaucoma, Eds. R. Pittscrick, A.D.S. Caldwell, Academic Press, New York, ppO 98-107 (1980), are substituted for the normotensive rabbits.
Each of the test compounds exhibit intraocular pressure-lowering activity in this model.
- 1 5 ~ 88~4 ~ o ~ ~Ln ~ ~r D
~ ~ ~ 1--1` C~
U~
g O O
O W ~ ~
D~1 ~:
m o ol ~ o ~: ~ ~ u~
O . . .
n ' ~D O ~ ~ ~ ~a~
~ D 0 tl4 0 .,, E~
0 D ~
m ~ ,, m ~ a o a li3 0 O O O O
,,u~ a ~ ~ O O O o O
Z ~ ~ ~ ~ ~ ~r W~ ~ ~
o o :a~ ~ tY; a 'tS ~ E~l a H E-~ ~ ~~:
U~ ~ ~ 1 O
Z ~ ~ a~ JJ
~ ~ ~P O O O . O
O ~ O O O O ~1 0 a ~; O ~D ~ ~ ~ ~ --a ~: ,, ~n C~ ~;
~ ~ ~ SJ
~ ~ ~ u~ 0~5 O . . . ~ ~
o 0 Z ~
m ~ a~
~ ~D O O 1` ~D
O
~ I~
0~
Z ~ ~
~ 5~ H ~
O st~ H1--1~> 0 ~ X H
a
Claims (29)
1. An ophthalmologic composition for the topical treatment of glaucoma or lowering of intraocular pres-sure which comprises an intraocular pressure-lowering effective amount of a compound of the formula:
wherein R is lower alkyl, lower cycloalkyl, lower al-kenyl, lower alkynyl, lower alkyl or aryl carboxymethyl, lower haloalkyl, aryl, or aralkyl; A is a direct bond, lower alkylenyl or lower alkenyl; x is an integer from 1 to 3, provided that when x is greater than 1, differ-ent occurrences of the group may be the same or different; Ar is unsubstituted aromatic or aromatic sub-stituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, acetamido, amino, nitro, lower al-kylamino, hydroxy, lower hydroxyalkyl, or cyano; R1 is lower alkyl, lower hydroxyalkyl, lower pharmaceutically acceptable salt thereof and an ophthalmologically accept-able carrier.
wherein R is lower alkyl, lower cycloalkyl, lower al-kenyl, lower alkynyl, lower alkyl or aryl carboxymethyl, lower haloalkyl, aryl, or aralkyl; A is a direct bond, lower alkylenyl or lower alkenyl; x is an integer from 1 to 3, provided that when x is greater than 1, differ-ent occurrences of the group may be the same or different; Ar is unsubstituted aromatic or aromatic sub-stituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, acetamido, amino, nitro, lower al-kylamino, hydroxy, lower hydroxyalkyl, or cyano; R1 is lower alkyl, lower hydroxyalkyl, lower pharmaceutically acceptable salt thereof and an ophthalmologically accept-able carrier.
2. The composition of claim 1, wherein A is a di-rect bond, an alkylenyl group of from 1 to 5 carbon at-oms or alkenyl of from 2 to about 5 carbon atoms; and x is 1 or 2.
3. The composition of claim 1, wherein Ar is phenyl;
x is 1 or 2; A is a direct bond, an alkylenyl group of from 1 to about 3 carbon atoms, or alkenyl of from 2 to about 3 carbon atoms and at least one of the groups is in the ortho position with respect to the group.
x is 1 or 2; A is a direct bond, an alkylenyl group of from 1 to about 3 carbon atoms, or alkenyl of from 2 to about 3 carbon atoms and at least one of the groups is in the ortho position with respect to the group.
4. The composition of claim 1, wherein Ar is phenyl;
x is 1 or 2; A is alkylenyl of from 1 to about 3 carbon atoms, and at least one of the groups is in the para position with respect to the group.
x is 1 or 2; A is alkylenyl of from 1 to about 3 carbon atoms, and at least one of the groups is in the para position with respect to the group.
5. The composition of claim 3 or 4, wherein R is lower alkyl of from 1 to about 5 carbon atoms.
6. The composition of claim 1, wherein the compound is of the formula:
wherein A is an alkylene group of from 1 to about 3 car-bon atoms, or alkenyl of from 3 to about 5 carbon atoms;
R is lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, or lower alky-nyl of from 3 to about 5 carbon atoms; Y is hydrogen, lower alkyl of from 1 to about 5 carbon atoms, lower al-kenyl of from 2 to about 5 carbon atoms, lower alkynyl of from 2 to about 5 carbon atoms, lower alkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitro, lower alkylamino of from 1 to about 5 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms or cyano; and R1 is lower alkyl of from 1 to about 5 carbon atoms, lower hydroxyalkyl of from 2 to about 5 carbon at-oms, lower alkenyl of from 3 to about 5 carbon atoms, or aralkyl wherein the alkyl portion contains from 1 -to about 5 carbon atoms and the aryl portion contains from 6 to about 10 carbon atoms.
wherein A is an alkylene group of from 1 to about 3 car-bon atoms, or alkenyl of from 3 to about 5 carbon atoms;
R is lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, or lower alky-nyl of from 3 to about 5 carbon atoms; Y is hydrogen, lower alkyl of from 1 to about 5 carbon atoms, lower al-kenyl of from 2 to about 5 carbon atoms, lower alkynyl of from 2 to about 5 carbon atoms, lower alkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitro, lower alkylamino of from 1 to about 5 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms or cyano; and R1 is lower alkyl of from 1 to about 5 carbon atoms, lower hydroxyalkyl of from 2 to about 5 carbon at-oms, lower alkenyl of from 3 to about 5 carbon atoms, or aralkyl wherein the alkyl portion contains from 1 -to about 5 carbon atoms and the aryl portion contains from 6 to about 10 carbon atoms.
7. The composition of claim 1, wherein the compound is of the formula:
wherein A is alkylenyl of from 1 to about 3 carbon atoms;
R is lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms or lower alky-nyl of from 3 to about 5 carbon atoms; Y is hydrogen, low-er alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkynyl of from 2 to about 5 carbon atoms, lower alkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitro, lower alkylamino of from 1 to about 5 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms or cyano; and R1 is lower alkyl of from 1 to about 5 carbon atoms, lower hydroxyalkyl of from 2 to about 5 carbon at-oms, lower alkynyl of from 3 to about 5 carbon atoms, or aralkyl wherein the alkyl portion contains from 1 to about 5 carbon atoms and the aryl portion contains from 6 to about 10 carbon atoms.
wherein A is alkylenyl of from 1 to about 3 carbon atoms;
R is lower alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms or lower alky-nyl of from 3 to about 5 carbon atoms; Y is hydrogen, low-er alkyl of from 1 to about 5 carbon atoms, lower alkenyl of from 2 to about 5 carbon atoms, lower alkynyl of from 2 to about 5 carbon atoms, lower alkoxy of from 1 to about 5 carbon atoms, halogen, acetamido, amino, nitro, lower alkylamino of from 1 to about 5 carbon atoms, hydroxy, lower hydroxyalkyl of from 1 to about 5 carbon atoms or cyano; and R1 is lower alkyl of from 1 to about 5 carbon atoms, lower hydroxyalkyl of from 2 to about 5 carbon at-oms, lower alkynyl of from 3 to about 5 carbon atoms, or aralkyl wherein the alkyl portion contains from 1 to about 5 carbon atoms and the aryl portion contains from 6 to about 10 carbon atoms.
8. The composition of claim 1, wherein the applied compound is:
wherein R is methyl, ethyl or propargyl, and R1 is iso-propyl, t-butyl, hydroxy-t-butyl, dimethyl propargyl, or 3,4-dimethoxyphenethyl.
wherein R is methyl, ethyl or propargyl, and R1 is iso-propyl, t-butyl, hydroxy-t-butyl, dimethyl propargyl, or 3,4-dimethoxyphenethyl.
9. The composition of claim 8, wherein R is ethyl, and R1 is isopropyl or t-butyl.
10. The composition of claim 1, wherein the applied compound is:
wherein R is methyl, ethyl or propargyl, and R1 is iso-propyl, t-butyl, hydroxy-t-butyl, dimethylpropargyl, or 3,4-dimethoxyphenethyl.
wherein R is methyl, ethyl or propargyl, and R1 is iso-propyl, t-butyl, hydroxy-t-butyl, dimethylpropargyl, or 3,4-dimethoxyphenethyl.
11. The composition of claim 10, wherein R is methyl, and R1 is isopropyl or t-butyl.
12. The composition of claim 10, wherein R is ethyl, and R1 is isopropyl or t-butyl.
13. The composition of claim 7, wherein R is cyclo-propylmethyl or propargyl; R1 is isopropyl or t-butyl; Y
is hydrogen; and A is ethylene.
is hydrogen; and A is ethylene.
14. The composition of claim 1, wherein the compound is:
wherein R is methyl, ethyl, or propargyl; R1 is isopropyl, t-butyl, hydroxy-t-butyl, dimethylpropargyl, or 3,4-dimethoxyphenethyl.
wherein R is methyl, ethyl, or propargyl; R1 is isopropyl, t-butyl, hydroxy-t-butyl, dimethylpropargyl, or 3,4-dimethoxyphenethyl.
15. The composition of claim 1, wherein the compound is:
wherein R is methyl, ethyl, or propargyl; R1 is isopropyl, t-butyl, hydroxy-t-butyl, dimethylpropargyl, or 3,4-dimeth-oxyphenethyl.
wherein R is methyl, ethyl, or propargyl; R1 is isopropyl, t-butyl, hydroxy-t-butyl, dimethylpropargyl, or 3,4-dimeth-oxyphenethyl.
16. The composition of claim 1, wherein the ophthal-mologically acceptable carrier is a sterile, buffered, aqueous isotonic solution.
17. The composition of claim 6, wherein the ophthal-mologically acceptable carrier is a sterile, buffered, aqueous isotonic solution.
18. The composition of claim 7, wherein the ophthal-mologically acceptable carrier is a sterile, buffered, aqueous isotonic solution.
19. The composition of claim 8, wherein the ophthal-mologically acceptable carrier is a sterile, buffered, aqueous isotonic solution.
20. The composition of claim 10, wherein the ophthal-mologically acceptable carrier is a sterile, buffered, aqueous isotonic solution.
21. The composition of claim 14, wherein the ophthal-mologically acceptable carrier is a sterile, buffered, aqueous isotonic solution.
22. The composition of claim 16, 17 or 18, further comprising a preserving agent selected from the group consisting of quaternary ammonium compounds, phenylmer-curic salts, thimerosal, methyl paraben, propyl paraben, benzyl alcohol and phenyl ethanol.
23. The composition of claim 19, 20 or 21, further comprising a preserving agent selected from the group consisting of quaternary ammonium compounds, phenylmer-curic salts, thimerosal, methyl paraben, propyl paraben, benzyl alcohol and phenyl ethanol.
24. The composition of claim 16, 17 or 18, further comprising a preserving agent selected from the group consisting of quaternary ammonium compounds, phenylmer-curic salts, thimerosal, methyl paraben, propyl paraben, benzyl alcohol and phenyl ethanol, and further compris-ing ethyl cellulose, polyvinylpyrrolidone, or polyethyl-ene glycol.
25. The composition of claim 19, 20 or 21, further comprising a preserving agent selected from the group consisting of quaternary ammonium compounds, phenylmer-curic salts, thimerosal, methyl paraben, propyl paraben, benzyl alcohol and phenyl ethanol, and further compris-ing ethyl cellulose, polyvinylpyrrolidone, or polyethyl-ene glycol.
26. The composition of claim 16, 17 or 18, wherein the compound is presenting a concentration of from about 0.01% to about 10% by weight.
27. The composition of claim 19, 20 or 21, wherein the compound is presenting a concentration of from about 0.01% to about 10% by weight.
28. The composition of claim 16, 17 or 18, further comprising a preserving agent selected from the group consisting of quaternary ammonium compounds, phenylmer-curic salts, thimerosal, methyl paraben, propyl paraben, benzyl alcohol and phenyl ethanol, wherein the compound is present in a concentration of from about 0.5% to about 5% by weight.
29. The composition of claim 19, 20 or 21, further comprising a preserving agent selected from the group consisting of quaternary ammonium compounds, phenylmer-curic salts, thimerosal, methyl paraben, propyl paraben, benzyl alcohol and phenyl ethanol, wherein the compound is present in a concentration of from about 0.5% to about 5% by weight.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US276,658 | 1981-06-23 | ||
US06/276,658 US4454154A (en) | 1981-06-23 | 1981-06-23 | Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents |
Publications (1)
Publication Number | Publication Date |
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CA1188224A true CA1188224A (en) | 1985-06-04 |
Family
ID=23057573
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000405136A Expired CA1188224A (en) | 1981-06-23 | 1982-06-14 | Compositions for treating glaucoma |
Country Status (17)
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US (1) | US4454154A (en) |
EP (1) | EP0082873B1 (en) |
JP (1) | JPH0653663B2 (en) |
AU (1) | AU565752B2 (en) |
CA (1) | CA1188224A (en) |
CH (1) | CH654205A5 (en) |
ES (1) | ES8401928A1 (en) |
GB (1) | GB2111387B (en) |
GR (1) | GR76847B (en) |
IL (1) | IL66070A (en) |
IT (1) | IT1156058B (en) |
NL (1) | NL8220252A (en) |
NZ (1) | NZ200972A (en) |
PH (1) | PH18970A (en) |
SE (1) | SE462075B (en) |
WO (1) | WO1983000014A1 (en) |
ZA (1) | ZA824340B (en) |
Families Citing this family (10)
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US5135926A (en) * | 1984-03-14 | 1992-08-04 | Bodor Nicholas S | Soft β-adrenergic blocking agents |
US5202347A (en) * | 1984-03-14 | 1993-04-13 | Bodor Nicholas S | Soft β-adrenergic blocking agents |
US5334601A (en) * | 1984-03-14 | 1994-08-02 | Bodor Nicholas S | Soft β-adrenergic blocking agents |
US4609663A (en) * | 1984-09-11 | 1986-09-02 | Alcon Laboratories, Inc. | Aldose reductase inhibitors useful in glaucoma therapy |
ATE76750T1 (en) * | 1987-04-03 | 1992-06-15 | Univ Columbia | USE OF A PROSTAGLANDIN MIXED WITH AN ADRENEGIC BLOCKER TO REDUCE INTERNAL EYE PRESSURE. |
CA1334168C (en) * | 1988-04-26 | 1995-01-31 | Louis M. De Santis | Antiglaucoma compositions containing combinations of .alpha.-2 agonists and .beta. blockers |
US4857552A (en) * | 1988-06-08 | 1989-08-15 | E. I. Du Pont De Nemours And Co. | Stable pharmaceutical composition |
US5536749A (en) * | 1994-10-13 | 1996-07-16 | Sl Pharmaceuticals, Inc. | Method for attenuation of sympathetic nervous system activity or onset of migraine by selectively metabolized beta-blocking agents |
US6197817B1 (en) | 1999-01-22 | 2001-03-06 | Selectus Pharmaceuticals, Inc. | Phenylpropionic acids and esters: compounds and methods for inducing beta-blockade for the treatment of cardiac disorders |
CA2565321A1 (en) * | 2004-05-25 | 2005-12-08 | Othera Pharmaceuticals, Inc. | Oculoselective drugs and prodrugs |
Family Cites Families (22)
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DE1593762A1 (en) * | 1967-02-06 | 1972-06-08 | Boehringer Sohn Ingelheim | Process for the preparation of new substituted 1-phenoxy-2-hydroxy-3-alkylaminopropanes |
US3868460A (en) * | 1967-02-06 | 1975-02-25 | Boehringer Sohn Ingelheim | Therapeutic compositions and method |
US3740444A (en) * | 1968-01-25 | 1973-06-19 | Boehringer Sohn Ingelheim | Therapeutic compositions and method |
GB1285038A (en) * | 1969-02-21 | 1972-08-09 | Ici Ltd | Alkanolamine derivatives |
DE1922003C3 (en) * | 1969-04-30 | 1979-10-11 | Boehringer Mannheim Gmbh, 6800 Mannheim | N- (3-aryloxy-2-hydroxypropyl) -aminocarboxylic acids, their esters, amides and salts, processes for the preparation of these compounds and their use in combating heart failure |
DE2048838A1 (en) * | 1970-10-05 | 1972-04-06 | C H Boehnnger Sohn, 6507 Ingel heim | New 1 phenoxy 2 hydroxy 3 hydroxyal kylaminopropane and process for their manufacture |
FR2132570B1 (en) * | 1971-04-09 | 1974-08-02 | Lipha | |
JPS4875539A (en) * | 1972-01-12 | 1973-10-11 | ||
JPS49247A (en) * | 1972-04-17 | 1974-01-05 | ||
US3839584A (en) * | 1972-08-31 | 1974-10-01 | Interx Research Corp | Pharmaceutical compositions containing a novel ester of ((methylamino)methyl)benzyl alcohol and methods of using same |
AT330150B (en) * | 1973-02-28 | 1976-06-10 | Boehringer Sohn Ingelheim | PROCESS FOR THE PREPARATION OF NEW 1-PHENOXY-2-HYDROXY -3- PROPARGYLAMINOPROPANES AND OF THEIR ACID ADDITION SALTS |
US3825583A (en) * | 1973-04-26 | 1974-07-23 | Interx Research Corp | Ester of 3-hydroxy-alpha-((methylamino)methyl)benzyl alcohol |
US4195085A (en) * | 1975-09-26 | 1980-03-25 | Merck & Co., Inc. | Compositions and methods for treating glaucoma by the topical administration of t-butylamino-3-(4-morpholino-1,2,5-thiadiazol-3-yloxy-2-phopanol hydrogen maleate |
US4146638A (en) * | 1976-02-17 | 1979-03-27 | Boehringer Ingelheim Gmbh | N-(3-phenoxy-2-hydroxy-propyl)-n-(2-phenyl-2-hydroxy-ethyl)-amines |
US4191765A (en) * | 1976-05-25 | 1980-03-04 | Hoechst Aktiengesellschaft | 1-Aryloxy-2-hydroxy-3-aminopropanes |
US4080471A (en) * | 1976-06-25 | 1978-03-21 | Aktiebolaget Hassle | Use of substituted isopropylaminopropanols for inducing inotropic effects of the human heart |
DE2752659A1 (en) * | 1976-12-07 | 1978-06-08 | Sandoz Ag | NEW TETRALINE DERIVATIVES, THEIR PRODUCTION AND USE |
US4127674A (en) * | 1977-03-21 | 1978-11-28 | Allergan Pharmaceuticals, Inc. | Method of treatment for glaucoma |
DE2962112D1 (en) * | 1978-02-08 | 1982-03-25 | Ici Plc | Alkanolamine derivatives, process for their preparation and pharmaceutical compositions containing them |
SE8004087L (en) * | 1980-06-02 | 1981-12-03 | Haessle Ab | NEW PARA-SUBSTITUTED 3-PHENOXY-1-ALKYLAMINOPROPANOL-2 WITH BETARETTY RECEPTOR BLOCKING PROPERTIES, AND PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME, AND METHOD OF ACCOUNTING ... |
SE8004088L (en) * | 1980-06-02 | 1981-12-03 | Haessle Ab | NEW SUBSTITUTED 3-PHENOXI-L-ALCOXICARBONYLALKYLAMINO-PROPANOL-2 WITH BETA-RECEPTOR BLOCKING PROPERTIES AND PROCEDURE FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS OF THE METHOD |
US4387103A (en) * | 1980-11-28 | 1983-06-07 | American Hospital Supply Corporation | Method for treatment or prophylaxis of cardiac disorders |
-
1981
- 1981-06-23 US US06/276,658 patent/US4454154A/en not_active Expired - Fee Related
-
1982
- 1982-06-14 CA CA000405136A patent/CA1188224A/en not_active Expired
- 1982-06-14 PH PH27416A patent/PH18970A/en unknown
- 1982-06-15 NZ NZ200972A patent/NZ200972A/en unknown
- 1982-06-16 IL IL66070A patent/IL66070A/en unknown
- 1982-06-18 GR GR68485A patent/GR76847B/el unknown
- 1982-06-18 ZA ZA824340A patent/ZA824340B/en unknown
- 1982-06-22 IT IT67796/82A patent/IT1156058B/en active
- 1982-06-23 EP EP82902333A patent/EP0082873B1/en not_active Expired
- 1982-06-23 AU AU87374/82A patent/AU565752B2/en not_active Ceased
- 1982-06-23 CH CH1102/83A patent/CH654205A5/en not_active IP Right Cessation
- 1982-06-23 ES ES513387A patent/ES8401928A1/en not_active Expired
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- 1982-06-23 JP JP57502293A patent/JPH0653663B2/en not_active Expired - Lifetime
- 1982-06-23 GB GB08303061A patent/GB2111387B/en not_active Expired
- 1982-06-23 WO PCT/US1982/000849 patent/WO1983000014A1/en active IP Right Grant
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1983
- 1983-02-18 SE SE8300913A patent/SE462075B/en not_active IP Right Cessation
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GR76847B (en) | 1984-09-04 |
PH18970A (en) | 1985-11-26 |
GB2111387A (en) | 1983-07-06 |
EP0082873B1 (en) | 1988-12-07 |
WO1983000014A1 (en) | 1983-01-06 |
IT1156058B (en) | 1987-01-28 |
IL66070A0 (en) | 1982-09-30 |
ES513387A0 (en) | 1984-01-01 |
JPS58500996A (en) | 1983-06-23 |
SE462075B (en) | 1990-05-07 |
GB8303061D0 (en) | 1983-03-09 |
US4454154A (en) | 1984-06-12 |
IL66070A (en) | 1987-03-31 |
SE8300913D0 (en) | 1983-02-18 |
AU565752B2 (en) | 1987-09-24 |
ZA824340B (en) | 1983-04-27 |
JPH0653663B2 (en) | 1994-07-20 |
NL8220252A (en) | 1983-05-02 |
NZ200972A (en) | 1986-10-08 |
IT8267796A0 (en) | 1982-06-22 |
GB2111387B (en) | 1986-02-05 |
EP0082873A4 (en) | 1983-11-11 |
ES8401928A1 (en) | 1984-01-01 |
SE8300913L (en) | 1983-02-18 |
CH654205A5 (en) | 1986-02-14 |
AU8737482A (en) | 1983-01-18 |
EP0082873A1 (en) | 1983-07-06 |
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